Recent years have seen a paradigm shift away from optimizing the brain:blood concentration ratio toward the more relevant brain:blood unbound concentration ratio (K) in CNS drug discovery. Here, we review the recent developments in the in silico and in vitro model systems to predict the K of discovery compounds with special emphasis on the in-vitro-in-vivo correlation. We also discuss clinical 'translation' of rodent K and highlight the future directions for improvement in brain penetration prediction. Important in this regard are in silico K models built on larger datasets of high quality, calibration and deeper understanding of experimental in vitro transporter systems, and better understanding of blood-brain barrier transporters and their in vivo relevance aside from P-gp and BCRP.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.drudis.2018.03.002 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Sensitive LC-MS/MS Methods for Amphotericin B Analysis in Cerebrospinal Fluid, Plasma, Plasma Ultrafiltrate, and Urine: Application to Clinical Pharmacokinetics.
Front Chem
November 2021
Department of Clinical Analyses, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
Article Synopsis
- Neurocryptococcosis, a type of meningoencephalitis, is treated with a combination of amphotericin B (AmB) and fluconazole.
- The study developed sensitive LC-MS/MS methods to measure AmB levels in cerebrospinal fluid (CSF) and plasma during treatment, successfully validating these methods for different sample types.
- Results showed that AmB concentrations in CSF were significantly lower than in plasma, with pharmacokinetic analyses highlighting changes in drug clearance and distribution throughout the treatment period.
Brain pharmacokinetics of two prolyl oligopeptidase inhibitors, JTP-4819 and KYP-2047, in the rat.
Basic Clin Pharmacol Toxicol
December 2011
School of Pharmacy, University of Eastern Finland, Kuopio.
Prolyl oligopeptidase (PREP) inhibitors are potential drug candidates for the treatment of neurological disorders, but little is known about their ability to cross the blood-brain barrier and to reach the target site. This study characterizes brain pharmacokinetics of two potent PREP inhibitors, JTP-4819 and KYP-2047. Firstly, the in vitro permeability (P(app) ) of JTP-4819 and KYP-2047 through a bovine brain microvessel endothelial cell monolayer was assessed.
View Article and Find Full Text PDFQSAR analysis of blood-brain distribution: the influence of plasma and brain tissue binding.
J Pharm Sci
June 2011
ACD/Labs, Inc, LT-08117 Vilnius, Lithuania.
The extent of brain delivery expressed as steady-state brain/blood distribution ratio (log BB) is the most frequently used parameter for characterizing central nervous system exposure of drugs and drug candidates. The aim of the current study was to propose a physicochemical QSAR model for log BB prediction. Model development involved the following steps: (i) A data set consisting of 470 experimental log BB values determined in rodents was compiled and verified to ensure that selected data represented drug disposition governed by passive diffusion across blood-brain barrier.
View Article and Find Full Text PDFComparison of in vitro cell models in predicting in vivo brain entry of drugs.
Int J Pharm
December 2010
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood-brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient (P(app)) determined in three in vitro cell models (BBMEC, Caco-2 and MDCKII-MDR1) for nine model drugs (alprenolol, atenolol, metoprolol, pindolol, entacapone, tolcapone, baclofen, midazolam and ondansetron) by using dual probe microdialysis in the rat brain and blood as an in vivo measure. There was a clear correlation between the P(app) and the unbound brain/blood ratios determined by in vivo microdialysis (BBMEC r=0.
View Article and Find Full Text PDFToward an improved prediction of human in vivo brain penetration.
Xenobiotica
December 2008
Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, UK.
The penetration of drugs into the central nervous system is a composite of both the rate of drug uptake across the blood-brain barrier and the extent of distribution into brain tissue compartments. Clinically, positron emission tomography (PET) is the primary technique for deriving information on drug biodistribution as well as target receptor occupancy. In contrast, rodent models have formed the basis for much of the current understanding of brain penetration within pharmaceutical Drug Discovery.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!